Benzyl ureas



United St te P will F 3,164,632 I .BENZYL UREAS Arthur Berger, Skokie, and Edeltraut E. Borgaes, Chicago, Ill., assignors to Baxter Laboratories Inc., Morton Grove, 11]., a corporation of Delaware No Drawing. Filed Feb. 4, 1963, Ser. No. 256,159

6 Claims. (Cl. 260-553) The present invention relates to novel organic benzyl ureas. More particularly, it relates to ring Substituted benzyl ureas of the formula:

' R2 0 R1 -CHr-I T-( i-N in WhlCh X is a member of the group consisting of halogen and lower alkyl,'R is selected from the group consisting of hydrogen and lower alkyl, R is a lower alkyl group, and R is hydrogen or a methyl group.

The novel compounds of the present invention possess unusual properties which render them useful in novel applications. Thesecornpounds generally show considerable central nervous system depressant activity in animals making them promising candidates'in thesearch for anticonvulsants, sedative andtran'quilizing agents;

The synthesis-of thesbenzyl mono alkyl ureas is usually eilected by reacting equirnolar quantities of the sub stituted amine 'with an isocyanate in the presence or absence of a solvent such as an alcohol, benzene or the chlorinated solvents. This reaction may be diagrammed as follows: i

. f I I @Cflz-NH RiNCO a p x f R3 /RI @C... l t H where the symbols X, R andR areas previously described. i When no solvent is used care must; be exercised because the reactionis usually very vigorous.

anate or vice versa Without affecting the yield which is usually very high. If a solventis employed it may be desirable to reflux the mixture to bringlthe, reaction to completion. 1

Isolation of theQnovel compounds: is usually quite simple as the novel benzyl ureas generally crystallize out upon cooling. If, however, the benzyl urea does not crystallize, it usually may be readily obtained'in solidformgbypartially or completely removing the solvent. A single recrystallization is usually then suflicient to provide 'rnaterial ofhigh purity. 7

The preparation of the novelbenzyl dialkylpreas of.

the present invention is accomplished by reacting the O'ccasionally cooling in ice is desirable to keep the reaction under "control. Either theamine may be added' to the isocy- 3,164,632 Patented Jan. 5, 1965 where the symbols X and R are as previously described and R is lower alkyl.

Occasionally, the above reaction proceeds to completion without heating. In some situations, however, it is desirable to reflux the mixture to insure completion of the reaction.

Illustrative of the variety of alkyl and halogen substituted benzyl amines which may be used in preparing the compounds of the present invention are 4-isopropyl benzyl amine," 2-chlor0benzylamine, Z-bromobenzylarnine, 4-

chloro-N-methylbenzylamine, 4-chlorobenzylamine and' Qcm-Nnosmam 411.0. 2NaOH i X L V Quin-minimum. NazSO4 51110 The following examples will-further serve to .illustrate the present invention: I

"EXAMPLE I V l Ethyl-ft-(Z-Methylbenzyl) Urea l o 3.6 g." (0.05 mole) of ethyl isocyanate in m1. of

, benzenewas slowly added with stirring 6.1 g: (0.05 mole) of 2-methylbenzylamiue. There was an immediate reaction and the product solidified while still quite liot. Recrystallization from absolute ethanol yielded 6.4 grams of white needles (.M.P,. l48-9) of l-ethyl-3-(2-methylbenzyl) urea; Y

' EXAMPLE II I-(Z-Bfbinobenzyl)-3-Methylurea To 5.2 g. 0.02 mole) 6f 1-(2-bromobenzyl)-3-methylappropriate benzyl amine with a substituted carbamyl v chloride in the presence or absence of solvents. This reaction may be diagrammed as follows:

at-.. M a

. i. (j /R Qantas-( i n j R1 2 thiourea in 100 ml. ofabsolute alcohol was added 140 ml; of l N sodium hydroxide. The mixture was heated to 7O",C., stirred continuously by means of a magnetic stirrerand ml. of 10% hydrogen peroxide added from a burette over a 30 minute period. On cooling a white solid separated out. It was recrystallized from benzene to yield 3 .8 g. of l-(2-bromobenzyl)-3emethylurea in the form ofwhite needles (M.P. 155). i

,ExAMPLuur" I-Allyl-3-(2-Chlorobertzyl) Urea- To a hot solution (70-80?) of 6.0 0.025 mole) of l-allyl-3-(Z-chlorobenzyl)-2-thiourea in 25 ml. of ethanol and ml. of 1 N sodium hydroxide, 60 ml. of 10% hydrogen peroxide was added dropwise with-agitation.

On cooling solid precipitated and 'was collected. After recrystallization from alcohol 3.4 g. (61% of the theo- 'retical) of white needles (M.P. -2 of l-allyl-3-(2- chlorobenzyl) urea A were isolated. EXAMPLEIV 1-nrButyl-3-(z-Fluorobenzyl) Urea To 6.25 g. (0.05 mole) of Z-fluorobenzyl amine stirred and cooled in, an icebath was added dropwiseiO g. (0.05

of 1-(2-methylbenzyl)-3-methylurea. The anticonvulsant activityof the compounds prepared above and that of the many related Compounds was determined'by administering the compounds intraperitoneally or orally to mice as a prophylactic against Pentylenetet-' v A razol (Met) induced and electro shock seizures v (MES);

mole) of n-butyl isocyanate. reaction and the product readily solidified. Recrystallization from isopropyl ether produced 9.5 g. (85% of the theoretical yield) of 1-n-butyl-3-(Z-fluorobenzyl) urea, light yellow needles (M.P. 635 1). 'An'additional 1.7 g. of crude product was obtained on evaporation 'of the isopropyl ether.

EXAMPLE V 1-(2-Chl0r0benzyl)3, 3-Dimethyl Urea To 21.2 g; (0.15 mole) of 2-chlorobenzylamine and 18 g. (0.18 mole) of triethylamine in 75 ml. of benzene was slowly added 16.2 g. (0.15 mole) of dimethylcarbamyl chloride in 25 ml. of benzene. The reaction apparently took .place very rapidly but to insure comple- There was 7 an immediate Suitable dosage formsforthe physiological testing of the novel compounds were prepared by either admixing a predetermined amount of the novel compound with a conventional solidpharmaceutical diluent and tableting the mixture or dissolving the compound in an acceptable parenteral fluid. It will, 'of course, be understood that a wide variety of other dosage forms may be prepared by combining the novel compound with-other acceptable pharmaceuticaldiluents and/o1" adjuvants.

10 In general, the compounds containing the'short chain alkyl groups are most effective as central nervous system depressants. Those compounds in which X is in the ortho position and equals Cl, Br, F or methyl; R is hydrogen or methyl, R is methyl or ethyl, and R is hydrogen, are especially preferred;

TABLE Compound ED5Q0IAED50 EDsoorAED LDQQOIALDED TDsuorATD MES i.p. (p0) MET i.p. (po) 7 Day i.p. (p0) I i.p. (p0) 1-(2-chlorobenzyl)-3-rnethylurea (101) 64 (92) 405 (510) "165 (560) I-(Z-methylbenZyl)-3-methylu.rea. 47 46 (11s) $530 (1550) (340) 1-(2-bromobenzyl)-3-1nethylu.roa 63(130) 44 (116) 500 1 150 (510) 1,-(2-fluorobenzyl)-3-n1ethylurea. 600 125 1,l-dimethyl-Ii-(Z-fluorobenzyl)-urea 600 1+(Z-chlorobenzyl)-3,3dimethylu.rea 38 (40) 38 (48) 600 1-ethyl-3-(2-fluor0benzyl) urea 700 1,1 dimethyl-Ii-(2-methylben7yl) urea- 44 (52) 44 (69) 500 (149) 1-(2 t-diehlorobenzyl) 3 3 dlrnethylure 57 43 (150) 250 270) 1-(2-bromobenzyl)-3,3-dirnethylurea 61 (94) 56 (106) 300 (295) 1-(2,5-dimethy1benzyl)-3-methylure 66 ,66 700 Q 1-(4-ehlorobenzyl) -3,li-dimethylurea 85: 85 300 I The AED D stands for the approximate dose and the E1350 is the more accurate dose in mgi/kg. which prevents convulsions in 50% of the mice tested; The ALD 1s the approximate dose and the L-Dso is'the more accurate do's'e which is-lethal for 50% of the mice. The AID is the approximate dose and the TDsu is the more accurate to'xio'dose for 50% of the mice by ther'otorod test. The approximate dose was-determined by testing less than the normal number of animals.

tion the mixture was refluxed for ab out"15 minutes, then allowed to cool to room temperatureQ 'Theprecipitated triethylamine hydrochloride was removedby 2 washings using 100 m1. of watereachtime. The benzene layer Was'dried over anhydrous sodium sulfate, then poured With stirring into 800ml. of petroleum ether.. .The white.

solid which formed was collected and had' Ml. 1037. V Onrecrystallization from carbon 'tetrachloride'18 g.

(5.6% of the theoretical, of .1-(2-chlorobenzy1)-3, 3 dimethylurea) (M12. 104.f6)-was obtained.

, EXAMPLE v1 1-(Z-Methylbenzyl)-3-Methylurea v I To 12.1 g. (0.1 mole) of Z-niethylbenzyl amine in 300 ml. of petroleum ether'cooled in an ice-salt bath was added slowly with stirring 6.0 g. (small excess) of methyl isocyanate in 50 ml. of petroleum ether. The tempera;

Some'of the more active compounds in the anticomvulsant'test 'areishown' inthe'accompanying table.

' What' We' claim is:.

1. A compound of the formula;

1 t me a. QOE-N-oAQ V in which X is a member of the group consisting of halogen and methyl,;R is selected from the group consisting of bas 1- 60 Weirnerz J. Chem. Soc; London, 101.1 17 (1920), 7

even-poet.)

References Cited in the file of this patent "Conant: Chem. of Organic Compounds, third edition (1947 page 332; 7

Boivin'et a1; Can. J. Chem. vol. 29 (1951), pages 47 8--8l. l

' Rowland et al.: J. Amer. Chem. Soc, vol. 73 (1951'),

pages 1046 53. L'Ifrivedi et al.':

A lnd. Chem. Soc... votes" (195 p es 6li u a 

1. A COMPOUND OF THE FORMULA: 